Acute Metabolic Effects of Exenatide in Patients With Type 1 Diabetes With and Without Residual Insulin to Oral and Intravenous Glucose Challenges

OBJECTIVE To evaluate the efficacy and safety of dasiglucagon – a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing – for treatment of severe hypoglycemia in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomized to receive a single subcutaneous dose of dasiglucagon 0.6 mg, placebo, or reconstituted glucagon 1 mg (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference. RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared to 40 (30, 40) minutes for placebo (P<0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 minutes in all but one participant (99%), superior to placebo (2%; P<0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20 and 30 minutes after dosing. The most frequent side effects were nausea and vomiting, as expected for glucagon treatment. CONCLUSIONS Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to that reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide a rapid and reliable treatment for severe hypoglycemia.

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Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02040 ◽

2017 ◽

Vol 103 (8) ◽

pp. 2870-2878 ◽

Cited By ~ 3

Author(s):

Maarit K Koskinen ◽

Johanna Lempainen ◽

Eliisa Löyttyniemi ◽

Olli Helminen ◽

Anne Hekkala ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Response ◽

Class Ii ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Intravenous Glucose ◽

Hla Dr ◽

Hla Genotype ◽

First Phase Insulin Response

Abstract Context A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

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Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review and meta‐analysis

Diabetes/Metabolism Research and Reviews ◽

10.1002/dmrr.3334 ◽

2020 ◽

Vol 36 (6) ◽

Cited By ~ 1

Author(s):

Ying‐Shan Liu ◽

Chu‐Na Chen ◽

Zhen‐Guo Chen ◽

Yu Peng ◽

Xiao‐Pu Lin ◽

...

Keyword(s):

Systematic Review ◽

Type 1 Diabetes ◽

Insulin Therapy ◽

Meta Analysis ◽

Metabolic Effects

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Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

Acta Endocrinologica ◽

10.1530/eje-13-0206 ◽

2013 ◽

Vol 169 (4) ◽

pp. 479-485 ◽

Cited By ~ 15

Author(s):

Heli T Siljander ◽

Robert Hermann ◽

Anne Hekkala ◽

Jyrki Lähde ◽

Laura Tanner ◽

...

Keyword(s):

Insulin Resistance ◽

Type 1 Diabetes ◽

Young Children ◽

Disease Susceptibility ◽

Insulin Response ◽

Diabetic Patients ◽

Model Assessment ◽

Β Cell ◽

Intravenous Glucose

ObjectiveReduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced β-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies.Design and methodsIntravenous glucose tolerance tests (IVGTTs) were carried out in 218 children withHLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed.ResultsChildren developing T1D were younger at seroconversion, progressed more rapidly to advanced β-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D.ConclusionsYoung age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children withHLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

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Dasiglucagon: A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia Results of Phase 3 Randomized Double-Blind Clinical Trial

10.2337/figshare.14207960 ◽

2021 ◽

Author(s):

Thomas R Pieber ◽

Ronnie Aronson ◽

Ulrike Hövelmann ◽

Julie Willard ◽

Leona Plum-Mörschel ◽

...

Keyword(s):

Type 1 Diabetes ◽

Plasma Glucose ◽

Severe Hypoglycemia ◽

Next Generation ◽

Double Blind ◽

Intravenous Glucose ◽

Subcutaneous Dose ◽

Double Blind Clinical Trial ◽

Glucose Recovery

OBJECTIVE To evaluate the efficacy and safety of dasiglucagon – a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing – for treatment of severe hypoglycemia in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomized to receive a single subcutaneous dose of dasiglucagon 0.6 mg, placebo, or reconstituted glucagon 1 mg (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference. RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared to 40 (30, 40) minutes for placebo (P<0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 minutes in all but one participant (99%), superior to placebo (2%; P<0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20 and 30 minutes after dosing. The most frequent side effects were nausea and vomiting, as expected for glucagon treatment. CONCLUSIONS Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to that reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide a rapid and reliable treatment for severe hypoglycemia.

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